Using AtT-20/D16-16 mouse pituitary cells rich in corticotropins we found that there are many hormones that can stimulate the release of ACTH. These are corticotropin releasing factor (CRF), catecholamines and vasoactive intestinal peptide (VIP). Catecholamines release ACTH via a Beta2-adrenergic receptor mechanism. The receptor mediated release of ACTH by these hormones act by generating cyclic AMP. ACTH liberates glucocorticoids which, in turn, inhibit the CRF, catecholamines and VIP mediated release of ACTH in AtT-20/D16-16 cells. Somatostatin also blocks the release of the receptor mediated release of ACTH by blocking the action of adenylate cyclase. Pretreatment of AtT-20/D16-16 cells with the Beta-adrenergic agonist markedly reduces the release of ACTH by catecholamines. A similar desensitization of ACTH release by CRF in primary pituitary cells was found. A desensitization of the inhibitory effects of somatostatin to receptor mediated ACTH was observed. We have found that isoproterenol can cause the secretion of ACTH in the rat by directly stimulating the Beta2-adrenergic receptors on the anterior pituitary. The catecholamine stimulated release of ACTH in vivo can be blocked by glucocorticoids. These observations show that the three stress hormones, catecholamines, ACTH and glucocorticoids, are interrelated and should have important implications in understanding different types of stress.